Targeted imaging of cancer remains an important but elusive goal. Such imaging could provide early diagnosis, detection of metastasis, aid treatment planning and benefit therapeutic monitoring. By leveraging the expanding list of specific molecular characteristics of tumors and their microenvironment, molecular imaging also has the potential to generate tumor-specific reagents. But many efforts at tumor-specific imaging are fraught by nonspecific localization of the putative targeted agents, eliciting unacceptably high background noise.
While investigators use many strategies to provide tumor-specific imaging agents—largely in the service of maintaining high target-to-background ratios—they fall into two general categories, namely direct and indirect methods (Blasberg & Tjuvajev (2003) J. Clin. Invest. 111:1620-1629). Direct methods employ an agent that reports directly on a specific parameter, such as a receptor, transporter or enzyme concentration, usually by binding directly to the target protein. Indirect methods use a reporter transgene strategy, in analogy to the use of green fluorescent protein (GFP) in vitro, to provide a read-out on cellular processes occurring in vivo by use of an external imaging device. Molecular-genetic imaging employs an indirect technique that has enabled the visualization and quantification of the activity of a variety of gene promoters, transcription factors and key enzymes involved in disease processes and therapeutics in vivo including Gli (Zhang (2007) Cancer Res. 67:9389-9397), E2F1 (Uhrbom et al. (2004) Nat. Med. 10:1257-1260), telomerase (Kishimoto et al. (2006) Nat. Med. 12:1213-1219; Padmanabhan et al. (2006) J. Nucl. Med. 47:270-277), and several kinases, including one that has proved useful in human gene therapy trials (Freytag et al. (2007) Mol. Ther. 15:1016-1023; Yaghoubi et al. (2009) Nat. Clin. Pract. Oncol. 6:53-58). Unfortunately, these techniques have been limited by problems relating to insufficient specific localization of imaging agents and unacceptably high background noise.
The presently disclosed subject matter relates to tripartite cancer theranostic nucleic acid constructs. Such nucleic acid constructs permit simultaneous cancer-specific viral replication, expression of a diagnostic gene product, and expression of a therapeutic gene.